2,3,4,4A-Tetrahydro-1H-pyrazino[1,2]quinoxalin-5(6)-ones and derivatives thereof

ABSTRACT

Compounds of the formula ##STR1## WHEREIN R is hydrogen (lower)alkyl, phen(lower)-alkyl, benzoyl(lower)alkyl, or p-halobenzoyl-(lower)alkyl; R 1  is hydrogen or (lower)alkyl; R 2  is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine, trifluoromethyl, or amino in the 7-, 8-, or 9-position; R 3  is hydrogen, or (lower)alkyl; and R 4  is hydrogen, (lower)-alkyl, (lower)alkoxy, chlorine, fluorine, or trifluoromethyl in the 7-, 8-, or 9-position; or the non-toxic acid addition salts thereof; exert a hyptotensive effect in hypertensive animals.

This is a continuation-in-part of application Ser. No. 668,872, filedMar. 22, 1976, now U.S. Pat. No. 4,032,639.

The present invention relates to substituted2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-ones andsubstituted 2,3,4,4a,5,6 ,hexahydro-1H-pyrazino[1,2-a]quinoxalines,which compounds have pharmacological activity. Also contemplated by thisinvention are intermediates used in the synthesis of said compounds, andmethods of use.

This invention comprises chemical compounds of the formula ##STR2##WHEREIN: R is hydrogen, (lower)alkyl, phen(lower)alkyl,benzoyl(lower)alkyl, or p-halobenzoyl(lower)alkyl;

R¹ is hydrogen or (lower)alkyl;

R² is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine,trifluoromethyl, or amino in the 7-, 8-, or 9-position;

R³ is hydrogen or (lower)alkyl; and

R⁴ is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine, ortrifluoromethyl in the 7-, 8-, or 9-position; or the non-toxic acidaddition salts thereof;

The compounds of Formula Ia or Ib exert a hypotensive effect inhypertensive warm-blooded animals, as evidenced by pharmacologicalevaluation in standard test procedures.

In subgeneric aspects, this invention contemplates the followingpreferred embodiments:

A compound of Formula Ia wherein R and R¹ are each hydrogen and R² hasthe meanings defined hereinabove.

The compound of Formula Ia wherein R, R¹, and R² are each hydrogen.

A compound of Formula Ia wherein R is hydrogen, R¹ is (lower)alkyl, andR² has the meanings defined hereinabove.

A compound of Formula Ia wherein R is (lower)alkyl, phen(lower)alkyl,benzoyl(lower)alkyl, or p-halobenzoyl(lower)alkyl; R¹ is hydrogen; andR² has the meanings defined hereinabove.

A compound of Formula Ia wherein R is (lower)alkyl, R¹ is hydrogen, andR² has the meanings defined hereinabove.

A compound of Formula Ib wherein R¹ and R³ are each hydrogen and R⁴ hasthe meanings defined hereinabove.

The compound of Formula Ib wherein R¹, R³, and R⁴ are each hydrogen.

A compound of Formula Ib wherein R¹ is (lower)alkyl, R³ is hydrogen, andR⁴ has the meanings defined hereinabove.

A compound of Formula Ib wherein R¹ is hydrogen, R³ is (lower)alkyl, andR⁴ has the meanings defined hereinabove.

A compound of Formula Ia wherein R and R² are each hydrogen and R¹ is(lower)alkyl.

A compound of Formula Ia wherein R¹ and R² are each hydrogen and R is(lower)alkyl, phen(lower)alkyl, benzoyl(lower)alkyl, orp-halobenzoyl(lower)alkyl.

A compound of Formula Ia wherein R¹ and R² are each hydrogen and R is(lower)alkyl.

A compound of Formula Ib wherein R³ and R⁴ are each hydrogen and R¹ is(lower)alkyl.

A compound of Formula Ib wherein R¹ and R⁴ are each hydrogen and R³ is(lower)alkyl.

Also within the scope of this invention are the intermediates employedin the synthesis of the compounds of Formula Ia. Such intermediates are:

(a) compounds of the formula: ##STR3## wherein: Y is (lower)alkyl orcarbobenzoxy; and

R² is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine,trifluoromethyl, or trifluoroacetamido in the 3-, 4-, or 5-position ofthe phenyl ring; or the salts thereof;

(b) compounds of the formula: ##STR4## wherein: R¹ is hydrogen or(lower)alkyl; and

R² is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine,trifluoromethyl, amino, or trifluoroacetamido in the 7-, 8-, or9-position;

(c) the compound which is 4-carbobenzoxypiperazine-2-carboxylic acid orthe salts thereof.

In the compounds of Formula Ia or Ib, the substituent represented by R²is substituted in the phenyl ring of the nucleus at either the 7-, 8-,or 9-position. The 9-position is preferred.

As used herein and in the claims the term "(lower)alkyl" means analiphatic hydrocarbon group containing up to three carbon atoms, i.e.the methyl, ethyl, propyl, or isopropyl groups. The methyl groups isespecially preferred. The term "(lower)-alkoxy" means an aliphatic ethergroup having up to three carbon atoms, i.e. methoxy, ethoxy, propoxy, orisopropoxy. The methoxy group is especially preferred. The term"phen(lower)-alkyl" means a group in which the phenyl group is attachedto an aliphatic hydrocarbon chain containing up to three carbon atoms,e.g. the benzyl, phenethyl, or phenpropyl groups. The term"benzoyl(lower)alkyl" means a group in which the benzoyl group isattached to an aliphatic hydrocarbon chain containing up to three carbonatoms, e.g. benzoylmethyl, benzoylethyl, or benzoylpropyl. The term"p-halobenzoyl(lower)alkyl means a benzoyl(lower)alkyl group in whichthe phenyl moiety thereof is substituted in the para position by afluorine or chlorine atom. The p-fluorobenzoylpropyl group is especiallypreferred. The term "o-nitrohalobenzene" means nitrobenzene containing afluorine, chlorine, or bromine atom in the ortho position.

The general method of synthesis of the compounds of Formula Ia isillustrated schematically in FIG. I of the annexed drawing which depictsthe preparation of2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one and thederivatives thereof containing a 3-methyl and/or 6-methyl group. In FIG.1, the symbol CBZ means a carbobenzoxy group: ##STR5## while Xrepresents a chlorine, fluorine, or bromine atom.

Referring now to FIG. 1, wherein the compounds are assigned Romannumerals for identification, in Process A,4-carbobenzoxypiperazine-2-carboxylic acid (II) is condensed with ao-nitrohalobenzene (III), to afford a4-carbobenzoxy-1-(o-nitrophenyl)piperazine-2-carboxylic acid (IV). Thereaction is carried out in an inert organic solvent, such asdimethylsulfoxide, in the presence of a base, such as triethylamine at atemperature from about 20° to about 100° C., preferably 90° C. Theo-nitrofluorobenzenes are preferred starting materials.

The intermediate IV is cyclized to a3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-one(V) by a two-step process involving reduction of the nitro group to theamino group followed by cyclization. The reduction step is preferablyperformed by treating a water solution of the sodium or other solublesalt of the nitro-acid (IV) with a suitable reducing agent, such assodium dithionite. The amino-acid thus produced is cyclized by adjustingthe pH of the solution to about 7.5 or less (preferably a pH of about3).

The 3-carbobenzoxy protecting group is removed from a3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one(V) by catalytic hydrogenation (Process C) to afford a2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-5(6H)-one (VI). Thehydrogenation is carried out in an inert solvent, such as ethanol, inthe presence of a catalyst, such as 10% palladium on carbon, at apressure of from about 1 atm. to about 3 atm., preferably about 3 atm.

If desired the hydrogenation may be performed in the presence ofhydrogen chloride which provides the product as the acid addition salt.Alternatively, intermediate IV can be reductively cyclized by catalytichydrogenation (Raney nickel), underwhich conditions the carbobenzoxygroup is also removed, to afford the product VI directly (Process I).

When it is desired to prepare a product containing a substituent at the3-position, a2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one (VI) istreated with a suitable alkylating agent (Process D), for example, analkyl halide. The reaction is performed in an inert solvent, such asethanol, preferably in the presence of a weak base, such as potassiumcarbonate. Other alkylating agents, such as the tosylate derivatives,will be apparent to those skilled in the art.

When it is desired to prepare a compound containing a substituent in the6-position, a3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one(V) is alkylated at the 6-position (Process E) and then catalyticallyhydrogenated (Process F) to remove the protecting 3-carbobenzoxy group.The alkylation is effected by contacting the intermediate (V) with astrong base, e.g. sodium hydride, in an inert solvent, e.g. dimethylformamide, and then adding the alkylating agent, e.g. a (lower)alkylhalide or tosylate. The 3-carbobenzoxy protecting group is removed bythe methods as hereinabove discussed.

When it is desired to prepare a product (X) containing substituents atboth the 3- and 6 -positions. the intermediate VII can be alkylated inthe 6-position (Process H) or the intermediate IX can be alkylated inthe 3-position(ProcessG) using the techniques hereinbefore described.

While the above method of synthesis has been described by reference toFIG. 1 which illustrates the preparation of2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one andderivatives thereof containing a 3-methyl and/or 6-methyl group, it willbe apparent to those skilled in the art of chemistry that any of thecompounds as variously substituted within the scope of Formula Ia may beprepared by this method or by modification of this method which would beobvious to those skilled in the art. Thus, compounds of Formula Iawherein R² is a group other than hydrogen may be prepared by employingthe appropriately substituted o-nitrohalobenzene in Process A and usingthe intermediates formed therefrom in the subsequent processes.

When it is desired to prepare a compound wherein R² is amino, the aminogroup in the starting nitrobenzene compound can be blocked to preventside reactions during the synthesis. The blocking group can be removedby standard techniques at a later stage of the process. Thetrifluoroacetyl group is conveniently used as a blocking group.

Compounds where R is phen(lower)alkyl, benzoyl(lower), alkyl, orp-halobenzoyl(lower)alkyl may be prepared by employing the appropriatelysubstituting alkylating agent in Processes D, E, H, or G, describedabove.

The compounds of Formula Ia wherein R is (lower)alkyl, are convenientlyprepared by an alternate process in which a4-(lower)alkylpiperazine-2-carboxylic acid is employed in place of4-carbobenzoxypiperazine-2-carboxylic acid (II) in Process A describedabove. Reduction of the nitro group of the product thus formed followedby cyclization (as in Process B, described above) directly gives thedesired 3-(lower)alkyl2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-ones without theneed for blocking and deblocking the piperazine nitrogen.

In the method of synthesis depicted in FIG. 1, the carbobenzoxy group isemployed as a blocking group to protect the reactive nitrogen of thepiperazine ring of the intermediates. It will be obvious to thoseskilled in the art that any conventional blocking group useful forprotecting a secondary amino group may be employed, for example, thebenzhydryl or benzyl group.

In general, the compounds of Formula Ia are converted to the compoundsof Formula Ib by reduction of the lactam carbonyl group of anappropriate intermediate or product. This can be effected using areducing agent which will reduce the lactam carbonyl without reducingother substituents. A particularly useful method is to treat2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one orderivatives thereof with lithium aluminum hydride in an inert solvent atan elevated temperature, for example, refluxing tetrahydrofuran.

4-Carbobenzoxypiperazine-2-carboxylic acid (II) employed as a startingmaterial in Process A is prepared from piperazine-2-carboxylic acid inthree steps: (a) treating said acid, as the dihydrochloride, with cupriccarbonate in water to form the cupric ion chelate; (b) treating thechelate with benzylchloroformate in acetone-water to introduce thecarbobenzoxy group; and (c) treating the3-carbobenzoxypiperazine-2-carboxylic acid, copper chelate withhydrochloric acid and hydrogen sulfide to destroy the chelate. Theproduct is isolated as the hydrochloride salt.

The o-nitrohalobenzenes employed as starting materials in the processdescribed above are either known compounds or may be prepared from knowncompounds by methods which will be apparent to one skilled in the art ofchemistry. The o-nitrofluorobenzenes are preferred starting materialssince the fluorine atom is more easily replaced than chlorine orbromine.

Since the compounds of Formula Ia or Ib possess an asymmetric carbonatom optical enantiomorphs are possible, and the compounds of theinvention may be in the form of the pure enantiomorph or mixturesthereof, such as the racemates.

The compounds of Formula Ia or Ib may be obtained in the form of thepure enantiomorph either by resolving a desired racemic product or byresolving a racemic starting material or intermedaite at any convenientstage of the synthesis. Methods of carrying out the resolution are wellknown in the art of chemistry. For example, the desired racemate may betreated with an optically active carboxylic acid and the opticallyactive addition salts may be separated by standard techniques.

The compounds of Formula Ia and Ib as obtained in the processes depictedin FIG. I, and the appropriate intermediates thereto, may be isolatedand purified in a conventional manner. It is furthermore appreciatedthat in the various processes hereinbefore described, factors such assolvents or temperatures are not critical and the selection of atemperature or solvent for a particular process will be apparent to oneskilled in the art.

The compounds of Formula Ia or Ib may exist either in the form of thefree base or the acid addition salt. Methods for converting one suchform to another will be obvious to one skilled in the art of chemistry.

The amino acids, 4-carbobenzoxypiperazine-2-carboxylic acid and the4-(substituted)-1-(o-nitrophenyl)piperazine-2-carboxylic acids, employedas intermediates for preparing the compounds of Formula Ia or Ib mayexist either in the acid, base, or zwitterion form, and methods forconverting one such form to another will be apparent to those skilled inthe art.

For pharmacological use, the compounds of Formula Ia or Ib may beadministered in the form of an acid addition salt of a non-toxic organicor inorganic acid. The salts may be prepared by methods well known inthe art. Appropriate salts are those formed from the following acids:hydrochloric, hydrobromic, sulfonic, sulfuric, phosporic, nitric,maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic,acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic,palmitic, itaconic, and benzenesulfonic.

In its method of use aspect, this invention provides a method forrelieving hypertension in warm-blooded animals which comprisesadministering to an animal in need thereof a hypotensive effectiveamount of a compound selected from the group consisting of:

2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one;

2,3,4,4a-tetrahydro-6-methyl-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one;

2,3,4,4a-tetrahydro-9-methoxy-1H-pyrazino[1,2a]quinoxalin-5-(6H)-one;

7-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2,-a]quinoxalin-5-(6H)-one;

8-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one;

9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one;

2,3,4,4a-tetrahydro-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one;

2,3,4,4a-tetrahydro-9-methyl-1H-pyrazino[[1,2-a]quinoxalin-5-(6H)-one;

7-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;

8-fluoro,2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one; or

9-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)one.

When employed to relieve hypertension, the effective dosage of thecompounds of Formula Ia or Ib will vary according to the particularcompound being employed, the severity and nature of the hypertension,and the particular subject being treated. In general, with largewarm-blooded animals (about 70 kg. body weight) effective results can beachieved by the oral route at a dosage level of from 25 mg. to about 2g. given as needed, for example every four to six hours. A dose of about25 mg. to about 500 mg. is preferred. Therapy should be initiated atlower dosages, the dosage thereafter being increased until the desiredhypotensive effect is obtained.

When employed as hypotensive agents, the active substances may beadministered alone or in combination with pharmaceutically acceptablecarriers, the proportion and nature of which are determined by thesolubility and chemical properties of the compound selected, the chosenroute of administration, and standard pharmaceutical practice. Forexample, the compounds of Formula Ia or Ib may be administered orally insolid dosage forms, e.g. capsules, tablets, or powders, or in liquidforms, e.g. solutions or suspensions. The compound may also be injectedparnterally in the form of sterile solutions or suspensions. Solid oralforms may contain conventional excipients, for instance: lactose,succrose, magnesium stearate, resins, and like materials. Liquid oralforms may contain various flavoring, coloring, preserving, stabilizing,solubizing, or suspending agents. Parenteral preparations are sterileaqueous or nonaqueous solutions or suspensions which may contain variouspreserving, stabilizing, buffering, solubilizing, or suspending agents.If desired, additives, such as saline or glucose may be added to makethe solutions isotonic.

The following examples are illustrative of the processes of theinvention. All temperatures are in centigrade.

EXAMPLE I 4-Methyl-1-(o-nitrophenyl)piperazine-2-carboxylic acid

A solution of 6.6 g. (0.164 mole) of sodium hydroxide, 28.2 g. (0.165mole) of ethyl-4-methylpiperazine-2-carboxylate, 20 ml. of water and 200ml. of ethanol is refluxed for 3 hours. This solution is then addedunder nitrogen to a hot stirred solution of o-nitrofluorobenzene in 300ml. of ethanol and 30 ml. of water. The resultant solution is refluxedfor 48 hours, cooled and filtered to give 12.8 g. of yellow product,m.p. 222-225°. Concentration of the mother liquors to ˜100 ml. andadjusting the pH to 6 yields an additional 6.6 g. of product. Furtherconcentration of mother liquors gives yet another 3 g. of product. Totalyield is 22.4 g., 51.5%. The analytical sample had m.p. 234° dec.

Analysis for: C₁₂ H₁₅ N₃ O₄.H₂ O

Calculated: 50.88; H, 6.05; N, 14.82.

Found: C, 51.67; H, 5.95; N, 15.15.

EXAMPLE II2,3,4,4a-Tetrahydro-3-methyl-1H-pyrazino[1,2-a]quinoxaline-5(6H)-one

A mixture of 3.5 g. (0.0135 mole) of4-methyl-1-(o-nitrophenyl)piperazine-2-carboxylic acid, 2.5 g. (0.025mole) of potassium bicarbonate, 110 ml. of water, 110 ml. of ethanol and21/2 teaspoons of Raney nickel is hydrogenated in a Parr apparatus for12 hours at an initial hydrogen pressure of 47 p.s.i. The catalyst isfiltered and the filtrate is acidified with dilute hydrochloric acid.The mixture is then basified with sodium hydroxide and extracted withethylacetate. The extract is dried and concentrated to give 2.3 g. ofproduct. This is treated with 1 equivalent of hydrogen chloride inethanol. After standing and cooling, filtration gives 2.4 g. of product,as the hydrochloride salt, m.p. 272-275°. Recrystallization of the saltfrom ethanol-water gives 1.75 g., m.p. 284-285° dec.

Analysis for: C₁₂ H₁₆ N₃ O.11/2 H₂ O

Calculated: C, 54.85; H, 6.52; N, 15.99.

Found: C, 54.86; H, 6.46; N, 15.82.

EXAMPLE III2,3,4,4a,5,6-Hexahydro-3-methyl-1H-pyrazino[1,2-a]quinoxaline

A mixture of 7.1 g. of2,3,4,4a-tetrahydro-3-methyl-1H-pyrazino[1,2,-a]quinoxalin-5-(6H)-one,3.5 g. of lithium aluminum hydride and 450 ml. of dry tetrahydrofuran isrefluxed for 20 hours under a nitrogen atmosphere. The mixture is cooledand 20 ml. of concentrated ammonium hydroxide is carefully added. Themixture is filtered and the filter cake is washed with isopropanol. Thefiltrate is concentrated to give 5.7 g. of product as a viscous oil. A3.5 g. portion is dissolved in acetone and treated with a saturatedsolution of fumaric acid in acetone. Filtration gives 3.3 g. of theproduct as the fumaric acid salt, m.p. 178°-188°. Recrystallization fromisopropanol gives 2.1 g. of salt, m.p. 186°-188°.

Analysis for: C₁₂ H₁₇ N₃.C₄ H₄ O₄

Calculated: C, 60.17; H, 6.63; N, 13.16.

Found: C, 60.01; H, 6.45; N, 12.68.

EXAMPLE IV 4-Carbobenzoxypiperazine-2-carboxylic Acid, Copper Chelate

To a stirred solution of 40.8 g. of piperazine-2-carboxylic acid,dihydrochloride in 700 ml. of water, is added slowly 48 g. of cupriccarbonate. The mixture is heated to boiling, then filtered hot. Aftercooling the deep blue filtrate is placed in a creased flask equippedwith efficient mechanical stirring and 60 g. of sodium bicarbonate iscautiously added with an additional 300 ml. H₂ O. To the stirred bluecopper complex solution is added slowly (about 1 hour) a solution of 45ml. of benzychloroformate (95%) in 700 ml. of acetone. The mixture wasstirred overnight (room temperature) and filtered. The plae blue solidis collected and washed with water (˜500 ml), ethanol (˜500 ml.), andether (˜500 ml.), then dried to give 60 g. of product, m.p. 222°-228°.

EXAMPLE V 4-Carbobenzoxypiperazine-2-carboxylic Acid, Hydrochloride

The pale blue copper complex (˜60 gm.) is placed in a flask equippedwith a gas inlet and mechanical stirring. One liter of water containing60 ml. of concentrated hydrochloric acid is added and gaseous hydrogensulfide then bubbled into the stirred mixture for 45 minutes at roomtemperature. The pale blue mixture turned black. When the hydrogensulfide treatment is completed, the gas inlet is connected to a nitrogentank and nitrogen is bubbled through the mixture for 1/2 hour at roomtemperature to remove remaining hydrogen sulfide. The mixture is thenfiltered through celite, with suction. The filter cake is washed with alittle water (75-100 ml.). The combined filtrates are brought to pH 7with concentrated NaOH, then concentrated on a rotary evaporator until awhite solid precipitated. The mixture is cooled and filtered. The sameprocess is repeated with successive filtrates until there is only asmall amount of filtrate volume remaining (˜75 to 100 ml. of yellowsolution). The collected white solids so obtained is placed in a flaskwith 1.5 liters of ethanol. The resulting suspension is acidified withethanolic hydrogen chloride, then stirred for 20 minutes at roomtemperature and filtered. The filtrate is concentrated to ˜350 ml.(crystallization begins) then cooled and filtered to give 26.5 g. ofproduct as the hydrochloride salt, m.p. 209°-212°. The mother liquorsare concentrated (˜125 ml.) cooled and filtered to yield an additional6.6 g. of product, m.p. 208°-212°. Further concentration to ˜50 ml.yields another 5.0 g. of product, m.p. 208°-211° dec. Total yield is38.1 g., 63% from piperazine-2-carboxylic acid.

EXAMPLE VI 4-Carbobenzoxy-1-(o-nitrophenyl)-piperazine-2-carboxylic acid

A mixture of 12.0 g. (0.04 mole) of4-carbobenzoxypiperazine-2-carboxylic acid, 8.4 g. (0.06 mole) ofo-nitrofluorobenzene, 16 g. of triethylamine and 100 ml. ofdimethylsulfoxide is heated at 90° for 8 1/2 hours, cooled, diluted withwater (300 ml.) and extracted with ether. The aqueous phase is thenacidified with dilute hydrochloric acid and extracted with ether. Thecombined ether extracts are diluted with 1/3 its volume of pentane. Theether-pentane solution is washed with water, dried (MgSO₄) andconcentrated to give 14 g. of yellow-orange glassy product. Thin layerchromatrgraphy analysis (1% acetic acid in benzene on a silica gelplate) shows 1 main spot with a faint second impurity spot.

EXAMPLE VII3-Carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one

To a solution of 13 g. of4-carbobenzoxy-1-(o-nitrophenyl)piperazine-2-carboxylic acid and 11.0 g.of sodium hydroxide in 200 ml. of water is added a solution of 20 g. ofsodium hydrosulfite in 200 ml. of H₂ O. The orange solution graduallyturns colorless over a period of 2-3 hours. Dilute hydrochloric acid isadded to bring the pH of the solution to about 3. A white precipitateforms. Stirring is continued for about 3-5 minutes, and the pH is raisedto about 7 by the addition of 40% sodium hydroxide. Filtration gives 8.6g. of product, m.p. 125°-140°. The analytical sample onrecrystallization from ethyl acetate hexane gave a m.p. 167°-170°.

Analysis for: C₁₉ H₁₉ N₃ O₃

Calculated: C, 67.64; H, 5.68; N, 12.46.

Found: C, 67.60; H, 5.67; N, 12.44.

EXAMPLE VIII 2,3,4,4a-Tetrahydro-1H-Pyrazino-[1,2-a]Quinoxalin-5(6H)-One

A mixture of 3.0 g. of 3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 2 g. of hydrogen chloride, 3 g. of10% palladium on carbon and 200 ml. of ethanol is hydrogenated on a Parrapparatus for 18 hours at 46 p. s. i. hydrogen pressure. The catalyst isfiltered and the filtrate is concentrated. The residue is recrystallizedfrom ethanol to give 0.55 g. of the product as the hydrogen chloridesalt, m.p. 288°-290°.

Analysis for: C₁₁ H₁₄ N₃ OCl

Calculated: C, 55.11; H, 5.87; N, 17.53.

Found: C, 54.44; H, 5.80; N, 17.43.

EXAMPLE IX2,3,4,4a-Tetrahydro-6-Methyl-1H-Pyrazino[1,2-a]Quinoxaline-5(6H)-One

To a stirred suspension of 0.87 g. (0.0180 mole) of sodium hydride (50%suspension in nujol) in 50 ml. of dimethyl formamide under a nitrogenatmosphere is added 5.5 g. (0.968 mole) of3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]-quinoxaline-5(6H)-one.The mixture is stirred 1/2 hours, then to it is added 4.5 g. of methyliodide in 10 ml. of dimethylformamide. The resultant mixture is stirredfor 1 hour, then poured into 100 ml. of water. The aqueous mixture isextracted with methylene chloride, dried (MgSO₄) and concentrated togive 5.7 g. of viscous glass. This glass is dissolved in 150 ml. ofethanol containing 0.3 g. of hydrogen chloride and hydrogenated over 5g. of 10% palladium on carbon for 5 1/2 hours at 45 p. s. i. hydrogenpressure with the temperature about 50°. The catalyst is filtered andthe filtrate is concentrated. Recrystallization of the residue fromethanol gives 1.9 g. of product as the hydrochloride salt, m.p.260°-264°.

Analysis for: C₁₂ H₁₅ N₃ 0.1/4H₂ O

Calculated: C, 55.81; H, 6.44; N, 16.27.

Found: C, 55.98; H, 6.55; N, 16.10.

EXAMPLE X2,3,4,4a-Tetrahydro-3-(2-Phenethyl)-1H-Pyrazino[1,2a]Quinoxaline-5(6H)-One

A mixture of 1.5 g. of2,3,4,4a-tetrahydro-1H-pyrazino-[1,2a]quinoxaline-5(6H)-one, 3 ml. ofphenethyl bromide, 2.0 g. of sodium iodide, 1.2 g. of potassiumcarbonate and 75 ml. acetone is refluxed for 20 hours under a nitrogenatmosphere. The mixture is concentrated, washed with ethyl acetate andfiltered. The ethyl acetate filtrate is acidified with hydrogen chlorideand filtered to give1.6 g. of light tan solid. Recrystallization of thesolid from ethanol-ether gives 1.1 g. of white solid product, m.p.260°-263° dec.

Analysis for: C₁₉ H₂₁ N₃ O.HCl.H₂ O

Calculated: C, 63.10; H, 6.63; N, 11.69.

Found: C, 62.78; H, 6.25; N, 11.60.

EXAMPLE XI3-[4-(4-Fluorophenyl)-4-Oxobutyl]-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

A mixture of 1.3 g. of2,3,4,4a-tetrahydro-1H-pyrazino-[1,2a]quinoxalin-5(6H)-one, 1.9 g.sodium iodide, 0.9 g. potassium carbonate, 2.6 g. of p-fluoro-γ-chlorobutyrophenone and 50 ml. of acetone is refluxed for 20 hours under anitrogen atmosphere. The reaction mixture is filtered and concentrated.The residue is washed with ethyl acetate and filtered. The filtrate isacidified with hydrogen chloride and filtered to give 1.5 g. of solidproduct, m.p. 140°-180° . Recrystallization of the solid fromethanol-ether gives 0.85 g. of product, m.p. 145°-150°.

Analysis for: C₂₁ H₂₃ N₃ O₂ FCl.1/2H₂ O

Calculated: C, 61.08; H, 5.85; N, 10.18.

Found: C, 60.59; H, 5.69; N, 10.20.

EXAMPLE XII4-Carbobenzoxy-1-(5-Methoxy-2-Nitrophenyl)Piperazine-2-Carboxylic Acid

By the same procedure described in Example VI, from 5.2 g. of2-fluoro-4-methoxy nitrobenzene and 6.01 of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, there isobtained 7.0 g. of product as an orange glass which is essentially pureby TLC analysis.

EXAMPLE XIII

3-Carbobenzoxy-2,3,4,4a-Tetrahydro-9-Methoxy-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One

By the same procedure described in Example VII, from 5.0 g. of4-carbobenzoxy-1-(5-methoxy-2-nitrophenyl)piperazine-2-carboxylic acidthere is obtained 3.1 g. of product, m.p. 167°-170°. Recrystallizationfrom ethyl acetate gives an analytical sample, m.p. 173°-174°.

Analysis for: C₂₀ H₂₁ N₃ O₄ :

Calculated: C, 65.38; H, 5.76; N, 11.44.

Found: C, 65.42; H, 5.80; N, 11.53.

EXAMPLE XIV2,3,4,4a-Tetrahydro-9-Methoxy-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VIII, from 3.2 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-9-methoxy-1H-pyrazino[1,2a]quinoxalin-5(6H)-onethere is obtained, on recrystallization from ethanol-water, 1.85 g. ofthe product as the hydrogen chloride salt, m.p. 275° dec.

Analysis for: C₁₂ H;hd 16N₃ O₂ CL

Calculated: C, 53.43; H, 5.98; N, 15.58.

Found: C, 53.00; H, 5.88; N, 15.38.

EXAMPLE XV4-Carbobenzoxy-1-(4-Chloro-2-Nitrophenyl)Piperazine-2-Carboxylic Acid

By the same procedure described in Example VI, from 6.25 g. of5-chloro-2-fluoronitrobenzene and 11 g. of 4-carbobenzoxypiperazin-Lb2-carboxylic acid, hydrochloride, there is obtained 9.5 g. of product asan orange glass which is essentially pure by TLC analysis.

EXAMPLE XVI3-Carbobenzoxy-8-Chloro-2,3,4,4a-Tegrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VII from 6.2 g. of4-carbobenzoxy-1-(4-chloro-2-nitrophenyl)piperazine-2-carboxylic acidthere is obtained 3.5 g. of product, m.p. 130°-140°, suitable forfurther use. In this case the product is isolated from the aqueousreaction mixture by extraction with ethyl acetate, drying the ethylacetate over magnesium sulfate and removing the solvent under vacuum.

EXAMPLE XVII8-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VIII, from 3.0 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-8-chloro-1H-pyrazino[1,2a]quinoxalin-5(6H)-onethere is obtained 0.95 g. of the product, as the hydrogen chloride salt,m.p. 210° dec. on recrystallization from ethanol.

Analysis for: C₁₁ H₁₃ N₃ OCl₂ . 3/4 H₂ O

Calculated: C, 45.94; H, 5.08; N, 14.61.

Found: C, 46.34; H, 5.07; N, 14.21.

EXAMPLE XVIII 2-Chloro-6-Fluoroaniline

To a stirred mixture of 20 g. of 2-chloro-6-fluorobenzoic acid, 100 ml.of chloroform and 50 ml. of concentrated sulfuric acid is added slowly10.2 g. of sodium azide while the temperature is kept at 40°-55°.Stirring is continued for 2 hours at 40°-55° then the mixture is pouredinto 500 ml. of ice water containing 80 g. of sodium hydroxide. Themixture is extracted with ether and the other extracts are dried overmagnesium sulfate. The dry extracts are then treated with hydrogenchloride, and the resultant product as the hydrochloride salt iscollected by filtration yielding 12.6 g. of white solid which sublimesat 160°-170°.

EXAMPLE XIX 2-Chloro-6-Fluoronitrobenzene

To a solution of 17.2 g. of 2-chloro-6-fluoroaniline hydrochloride and12.5 ml. of concentrated hydrochloric acid in 150 ml. of water is addedslowly a solution of 9 g. of sodium nitrite in 25 ml. of water. Thetemperature of the solution is kept below 5° at all times. This solutionis then added to a stirred suspension of 18 g. of cuprocupric sulfiteand 60 g. of sodium nitrite in 300 ml. of water at room temperature. Themixture is stirred for 1 hour then steam distilled until no trace ofproduct is noted condensing in the distillate. The distillate isextracted with ether, dried (magnesium sulfate) concentrated anddistilled to give 7.8 g. of product, b.p. 148°-152° at 30 mm. Gaschromatography analysis shows this to be greater than 95% pure.

EXAMPLE XX4-Carbobenzoxy-1-(3-Chloro-2-Nitrophenyl)Piperazine-2-Carboxylic Acid

By the same procedure described in Example VI, from 6.5 g. of2-chloro-6-fluoronitrobenzene and 12 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, there isobtained 9 g. of product as a pale yellow glass which is essentiallypure by TLC analysis.

EXAMPLE XXI3-Carbobenzoxy-7-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxaline-5(6H)-One

By the same procedure described in Example VII, from 4.5 g. of4-carbobenzoxy-1-(3-chloro-2-nitrophenyl)piperazine there is obtained3.5 g. of product, m.p. 178°-182°. Recrystallization from ethanol givesan analytical sample, m.p. 189°-191°.

Analysis for: C₁₉ H₁₈ N₃ O₃ Cl

Calculated: C, 61.37; H, 4.88; N, 11.30

Found: C, 60.81; H, 5.03; N, 11.27

EXAMPLE XXII7-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VIII, from 3.2 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-7-chloro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-onethere is obtained on recrystallization from ethanol-water 1.0 g. of theproduct as the hydrogen chloride salt, m.p. 270°-275° dec.

Analysis for: C₁₁ H₁₂ N₃ OCl.HCl.H₂ O

Calculated: C, 45,22; H, 5.18; N, 14.38.

Found: C, 45.55; H, 4.76; N, 14.41.

EXAMPLE XXIII 4-Fluoro-3-Nitrotoluene

By a procedure analogous to that described in Example XIX, from 10 g. of4-fluoro-3-aminotoluene there is obtained 4.2 g. of nitro product as apale yellow liquid, b.p. 105° to 110° at 25 mm.

EXAMPLE XXIV4-Carbobenzoxy-1-(4-Trifluoromethyl-2-Nitrophenyl)Piperazine-2-CarboxylineAcid

By a procedure analogous to that described in Example VI, from 10 g. of2-chloro-5-trifluoromethylnitrobenzene and 12 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, there isobtained 14 g. of product as a dark orange glass which is essentiallypure by TlC analysis.

EXAMPLE XXV2,3,4,4a-Tetrahydro-8-Trifluoromethyl-1H-Pyrazino[1,2-a]Quinoxaline-5(6H)-One

A solution of 7.5 g. of4-carbobenzoxy-1-(4-trifluoromethyl-2-nitrophenyl)piperazine-2-carboxylicacid, 4.0 g. of potassium bicarbonate, 150 ml. of water and 50 ml. ofethanol is hydrogenated over three teaspoons of Raney nickel catalyst at50 p. s. i. for 45 minutes. The catalyst is filtered and the filtrate isacidified and extracted with ethylacetate. The aqueous phase is thenbasified with dilute sodium hydroxide and extracted with ethyl acetate.Concentration of the organic phase gives 1.2 g. of pale yellow solidproduct, m.p. 193°-195°. This solid is converted to its hydrogenchloride salt in ethanol giving 0.78 g., m.p. 275°-277° dec.

Analysis for: C₁₂ H₁₂ N₃ OF₃. 1 1/4 H₂ O

Calculated: C, 59.26; H, 4.48; N, 10.37.

Found: C, 58.74; H, 4.61; N, 10.12.

EXAMPLE XXVI

3-Carbobenzoxy-2,3,4,4-Tetrahydro-8-Trifluoromethyl-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VII, from 3.5 g. of4-carbobenzoxy-1-(4-trifluoromethyl-2-nitrophenyl)piperazine-2-carboxylicacid there is obtained 1.2 g. of crude product with m.p. 170°-175°.Recrystallization from ethanol gives product with m.p. 201°-204°.

Analysis for: C₂₀ H₁₈ N₃ O₃ F₃

Calculated: C, 59.26; H, 4.48; N, 10.37.

Found: C, 58.74; H, 4.61; N, 10.12.

EXAMPLE XXVII4-Carbobenzoxy-1-(5-Chloro-2-Nitrophenyl)Piperazine-2-Carboxylic Acid

By a procedure analogous to that described in Example VI, from 7.7 g. of2,4-dichloronitrobenzene and 6.0 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride there isobtained 5.0 g. of yellow orange glass which showed one main yellow spotand one lesser spot on TLC analysis.

EXAMPLE XXVIII3-Carbobenzoxy-9-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VII, from 5.0 g. of4-carbobenzoxy-1-(5-chloro-2-nitrophenyl)piperazine-2-carboxylic acid,there is obtained 1.0 g. of product as a tan solid. Recrystallizationfrom ethanol gives product, m.p. 188°-191°.

EXAMPLE XXIX9-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VIII, from 1.9 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-9-chloro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onethere is obtained on recrystallization from ethanol 0.40 g. of theproduct as the hydrogen chloride salt, m.p. 300-303°.

Analysis for: C₁₁ H₁₂ N₃ OC1.H₂ O.1/8 C₂ H₅ OH

Calculated: C, 45.35; H, 5.33; N, 14.10

Found: C, 45.28; H, 4.90; N, 13.66

EXAMPLE XXX 2-Nitro-4-Trifluoroacetamidofluorobenzene

To a stirred solution of 7.8 g. of 4-fluoro-3-nitroaniline, 5.0 g. oftriethylamine in 150 ml. of methylene chloride is added dropwise 10.5 g.of trifluoroacetic anhydride at 5° to 10°. The mixture is stirred for0.5 hours, washed with water, dried and concentrated to give a brown oilwhich crystallizes. Recrystallization from benzene cyclohexane gives 5.3g. of product, m.p. 70°-75°.

EXAMPLE XXXI4-Carbobenzoxy-1-(2-nitro-4-Trifluoroacetamidophenyl)Piperazine-2-CarboxylicAcid

By a procedure analogous to that described in Example VI, from 5.0 g. of2-nitro-4-trifluoroacetamido fluorobenzene and 6.0 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride there isobtained 8.5 g. of yellow orange solid, m.p. 212°-215°. TLC analysisshows 1 spot.

EXAMAPLE XXXXII3Carbobenzoxy-2,3,4,4a-Tetrahydro-8-(2,2,2-Trifluoroacetamido)-1H-Pyrazino[1,2,-a]Quinoxalin-5(6H)-One

By a procedure analogous to that described in Example VII from 4.6 g. of4-carbobenzoxy-1-(2-nitro-2-trifluoroacetamido-phenyl)piperazine-2-carboxylicacid, there is obtained 3.6 g. of product, m.p. 255-262°.Recrystallization from ethanol-water gives 2.75 g., m.p. 264-265°.

Analysis for: C₂₁ H₁₉ N₄ O₄ F₃

Calculated: C, 56.24; H, 4.27; N, 12.50.

Found: C, 56.02; H, 4.46; N, 12.65.

EXAMPLE XXXIII2,3,3,4a-Tetrahydro-8-(2,2,2-Trifluoro-acetamido)-1H-Pyrazino[1,2-a]Quinoxalin-5-(6H)-One

By an analogous procedure to that described in Example VIII, from 2.2 g.of3-carbobenzoxy-2,3,4,4a-tetrahydro-8-(2,2,2-trifluoroacetamido)-1H-pyrazino1,2,-a]quinoxalin-5(6H)-onethere is obtained 0.46 g. of the product as the hydrogen chloride salt,m.p. 316-310° dec.

Analysis for: C₁₃ H₁₄ N₄ O₂ F₃ C1.1/2H₂ O

Calculated: C, 43.40; H, 4.20; N, 15.57.

Found: C, 43.64; H, 3.87; N, 15.35.

EXAMPLE XXXIV8Amino-3-Carbobenzoxy-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2,-a]Quinoxalin-5(6H)-One

A mixture of 2.8 g. of3-carbobenzoxy-2,3,4,4a-Tetrahydro-8-(2,2,2-trifluoroacetamido)-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one,0.5 g. sodium hydroxide and 200 ml. of water is boiled for 15 minutes,then cooled. The mixture is then extracted with methylene chloride. Theorganic portion is then extracted with dilute hydrochloric acid. Theaqueous acid phase is then basified with dilute sodium hydroxide andextracted with methylene chloride. The organic phase is dried andconcentrated to give 1.6 g. of pale yellow solid product, m.p. 130-135°.

EXAMPLE XXXV8-Amino-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5-(6H)-One

A mixture of 1.5 g. of8amino-3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one,1.5 g. of 10% Palladium on carbon catalyst and 150 ml. of ethanol ishydrogenated for 1/2 hour at 45 p.s.i. The catalyst is filtered and thefiltrate concentrated to a volume of 50 ml. Ethanolic hydrochloric acidis added, and the product precipitates as the hydrochloride salt. Weightof product 0.70 g., m.p. 294-295° dec. Recrystallization fromethanol-water gives 0.45 g. of pure product, m.p. 315-317° dec.

Analysis for: C₁₁ H₁₆ N₄ OCl₂

Calculated: C, 45.37; H, 5.54; N, 19.24.

Found: C, 45.25; H, 5.71; N, 18.80.

EXAMPLE XXXVI 4Carbobenzoxy-1-(5-Methyl-2-Nitrophenyl)-2-Carboxylic Acid

By a procedure analogous to that described in Example VI, from 7.0 g. of3-fluoro-4-nitrotoluene and 12.0 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, there isobtained 15.0 g. of yellow-orange glass which is essentially pure by TLCanalysis.

EXAMPLE XXXVII3-Carbobenzoxy-2,3,4,4a-Tetrahydro-9-Methyl-1H-Pyrazino[1,2-a]Quinoxalin-5-(6H)-One

By the same procedure described in Example VII from 15 g. of4-carbobenzoxy-1-(5-methyl-2-nitrophenyl)piperazine-2-carboxylic acidthere is obtained 8.00 g. of colorless product which onrecrystallization from ethanol gives product with m.p. 175-178°.

Analysis for: C₂₀ H₂₁ N₃ O₃ 1/2H₂ O

Calculated: C, 66.63; H, 6.15; N, 11.66.

Found: C, 66.16; H, 5.98; N, 11.45.

EXAMPLE XXXVIII2,3,4,4a-Tetrahydro-9-Methyl-1H-Pyrazino[1,2-a]Quinoxalin-5-(6H)-One

By the same procedure described in Example VIII from 6.0 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-9-methyl-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-onethere is obtained 0.93 g. of the hydrogen chloride salt of the productwith m.p. 195° dec.

Analysis for: C₁₂ H₁₆ N₃ O.HCl

Calculated: C, 56.80; H, 6.36; N, 16.56.

Found: C, 56.32; H, 6.28; N, 16.30.

EXAMPLE XXXIX 4-Carbobenzoxy-1-(4-Fluoro-2-Nitrophenyl)-2-CarboxylicAcid

By procedure analogous to that described in Example VI, from 6.5 g. of2,5-difluoronitrobenzene and 12.0 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, there isobtaine 14 g. of yellow-orange glass which is essentially pure by TLCanalysis.

EXAMPLE XL3-Carbobenzoxy-2,3,4,4a-Tetrahydro-8-Fluoro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

3-Carbobenzoxy-2,3,4,4a-tetrahydro-8-fluoro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-oneis prepared by essentially the same procedure described by Example VII.In this example, however, the product is extracted from the aqueousreaction mixture (after acidification) with ethyl acetate, dried andconcentrated to give 6 g. of crude product. Recrystallization of theproduct from ethanol gives 4.8 g. of product with m.p. 173-175°.

Analysis for: C₁₉ H₁₈ N₃ O₃ F

Calculated: C, 64.21; H, 5.12; N, 11.62.

Found: C, 63.97; H, 5.16; N, 11.69.

EXAMPLE XLI2,3,4,4a-Tetrahydro-8-Fluoro-1H-Pyrazino[1,2-a[Quinoxalin-5(6H)-One

By the same procedure described in Example VIII, from 4.5 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-8-fluoro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onethere is obtained 2.20 g. of the hydrogen chloride salt of the productwith m.p. 266-270° dec.

Analysis for: C₁₁ H₁₂ N₃ OF.HCl

Calculated: C, 51.26; H, 5.08; N, 16.30.

Found: C, 50.90; H, 5.19; N, 16.00.

EXAMPLE XLII

By procedures analogous to those described in Examples XXXIX, IX, andXLI, using 2,6-difluoronitrobenzene or 2,4-difluoronitrobenzene asstarting materials there are produced, respectively,2,3,4,4a-tetrahydro-7-fluoro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one and2,3,4,4a-tetrahydro-9-1H-pyrazino[1,2a]quinoxalin-5(6H)-one.

EXAMPLE XLIII3-Carbobenzoxy-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

A solution of 4-carbobenzoxy-1-(o-nitrophenyl)piperazine-2-carboxylicacid (Ex. VI), 28 gms. (0.073 mole) in 300 ml. ether was extracted with600 ml. (3 × 200 ml. portions) of aqueous 2% sodium bicarbonatesolution. The ether layer was then washed with 500 ml. water. Theaqueous layer was added to the bicarbonate extracts. The ether layer wasdiscarded. The combined aqueous extracts were diluted to 2 liters. Tothis stirred solution was added 30 gms. of sodium dithionite (Na₂ S₂O₄). The reddish solution turned nearly white and a precipitate formed(pH ˜7). After stirring for five minutes the pH was adjusted to ˜3 with20% HCl. The pH was raised to about 7, and the product was filtered,washed with cold water, and dried, yielding 15 gms. of product, m.p.168°-170°.

Analysis for: C₁₉ H₁₉ N₃ O₃

Calculated: C, 67.64; H, 5.68; N, 12.46.

Found: C, 67.44; H, 5.82; N, 12.30.

EXAMPLE XLIV4-Carbobenzoxy-1-(4-Methyl-2-Nitrophenyl)Piperazine-2-Carboxylic Acid

By a procedure analogous to that described in Example VI, from 4.0 g. of4-fluoro-3-nitrotoluene and 7.5 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, there isobtained 3.0 g. of product as an orange glass which is essentially pureby TLC analysis.

EXAMPLE XLV3-Carbobenzoxy-2,3,4,4a-Tetrahydro-8-Methyl-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VII from 3.0 g. of4-carbobenzoxy-1-(4-methyl-2-nitrophenyl)piperazine-2-carboxylic acidthere is obtained 1.7 g. of product as a pale yellow glass whichpartially crystallizes. TLC analysis shows only one spot.

EXAMPLE XLVI2,3,4,4a-Tetrahydro-8-Methyl-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

By the same procedure described in Example VIII from 1.6 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-8-methyl-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-onethere is obtained 0.60 g. of the hydrogen chloride salt of the productwith m.p. 296°-298° dec. on recrystallization from ethanol.

Analysis for: C₁₂ H₁₆ N₃ O .1/4 H₂ O

Calculated: C, 55.81; H, 6.44; N, 16.27.

Found: C, 55.82; H, 6.47; N, 15.92.

EXAMPLE XLVII

The antihypertensive effect of a compound of Formula Ia or Ib isellicited and demonstrated by administering the compound to ahypertensive rat and measuring the change in systolic blood pressure 2and 4 hours after administration. The rats used are either spontaneouslyhypertensive or are rendered hypertensive by applying a figure-of-eightligature around one kidney and contralateral nephrectomy. Malespontaneously hypertensive rats derived from the Okamoto-Aoki strainwere purchased from commercial breeders. In the renal hypertensive rats,blood pressure tends to stabilize at a hypertensive level afterapproximately six weeks. A group of at least 4 rats is given thecompound by the oral (P.O.) route. Systolic blood pressure, as measuredby an indirect technique using the Decker Caudal Plethysmorgraph, ismeasured prior to administration of the compound and at 2 and 4 hoursthereafter. This schedule may vary depending upon the behavior of thecompound. A control group of rats, given either a placebo or a standardantihypertensive agent is run with each group of treated rats.

The hypotensive activity of the compound is rated as follows:

    ______________________________________                                                         Systolic Decrease                                            Activity         in Blood Pressure                                            ______________________________________                                        Slight             25 - 35 mm Hg                                              Moderate           35 - 50                                                    Marked             over 50                                                    ______________________________________                                    

When tested as described above, the compounds of Formula Ia or Ib gavethe following results:

    ______________________________________                                        Compound                Activity (P.O.)                                       ______________________________________                                        2,3,4,4a-3-methyl-1H-pyrazino-                                                                        Moderate at                                           [1,2-a]quinoxalin-5(6H)-one                                                                           20 mg/kg *                                            2,3,4,4a,5,6-hexahydro-3-methyl                                                                       Moderate at                                           1H-pyrazino[1,2-a]quinoxaline                                                                         50 mg/kg *                                            2,3,4,4a-tetrahydro-3-(2-phenylethyl)-                                                                Moderate at                                           1H-pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                50 mg/kg **                                           3-[4-(4-fluorophenyl)-4-oxobutyl]-                                                                    Marked at                                             2,3,4,4a-tetrahydro-1H-pyrazino[1,2-                                                                  75 mg/kg *                                            a]quinoxalin-5(6H)-one                                                        2,3,4,4a-tetrahydro-6-methyl-1H-                                                                      Marked at                                             pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   5 mg/kg **                                            2,3,4,4a-tetrahydro-1H-pyrazino-                                                                      Marked at                                             [1,2-a]quinoxalin-5(6H)-one                                                                           2.5 mg/kg **                                          2,3,4,4a-tetrahydro-9-methoxy-1H-                                                                     Slight at                                             pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   10 mg/kg *                                            7-chloro-2,3,4,4a-tetrahydro-1H-                                                                      Moderate at                                           pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   10 mg/kg *                                            8-chloro-2,3,4,4a-tetrahydro-1H-                                                                      Slight at                                             pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   10 mg/kg *                                            9-chloro-2,3,4,4a-tetrahydro-1H-                                                                      Moderate at                                           pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   5 mg/kg **                                            2,3,4,4a-tetrahydro-8-trifluoromethyl-                                                                Slight at                                             1H-pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                5 mg/kg **                                            2,3,4,4a-tetrahydro-9-methyl-1H-                                                                      Slight at                                             pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   2.5 mg/kg **                                          2,3,4,4a-tetrahydro-8-methyl-1H-                                                                      Slight at                                             pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   10 mg/kg **                                                                   (at 24 hrs)                                           8-amino-2,3,4,4a-tetrahydro-1H-                                                                       Moderate at                                           pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   75 mg/kg;                                                                     Borderline at                                                                 25 mg/kg **                                           8-fluoro-2,3,4,4a-tetrahydro-1H-                                                                      Marked at                                             pyrazino[1,2-a]quinoxalin-5(6H)-one                                                                   2.5 mg/kg **                                           * in renal hypertensive rats                                                  ** in spontaneously hypertensive rats                                    

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R ishydrogen, (lower)alkyl, phen(lower)alkyl, benzoyl(lower)alkyl, orp-halobenzoyl(lower)alkyl;R¹ is hydrogen or (lower)alkyl; R² ishydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine,trifluoromethyl, or amino in the 7-, 8-, or 9-position; R³ is hydrogenor (lower)alkyl; and R⁴ is hydrogen, (lower)alkyl, (lower)alkoxy,chlorine, fluorine, or trifluoromethyl in the 7-, 8-, or 9-position; orthe non-toxic acid addition salts thereof.
 2. A compound as defined inclaim 1 of the formula: ##STR7## wherein R is hydrogen, (lower)alkyl,phen(lower)alkyl, benzoyl(lower)alkyl, or p-halobenzoyl(lower)alkyl;R¹is hydrogen or (lower)alkyl; R² is hydrogen, (lower)alkyl,(lower)alkoxy, chlorine, fluorine, trifluoromethyl, or amino in the 7-,8-, or 9-position; or the non-toxic acid addition salts thereof.
 3. Acompound as defined in claim 2 wherein R and R¹ are each hydrogen and R²is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine,trifluoromethyl, or amino.
 4. The compound as defined in claim 3 whichis 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.
 5. Acompound as defined in claim 3 wherein R² is (lower)alkyl,(lower)alkoxy, chlorine, fluorine, trifluoromethyl, or amino.
 6. Thecompound as defined in claim 5 which is7-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 7.The compound as defined in claim 5 which is8-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 8.The compound as defined in claim 5 which is9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 9.The compound as defined in claim 5 which is7-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 10.The compound as defined in claim 5 which is8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-one. 11.The compound as defined in claim 5 which is9-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 12.A compound as defined in claim 5 which is2,3,4,4a-tetrahydro-9-methoxy-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.13. A compound as defined in claim 5 which is2,3,4,4a-tetrahydro-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.14. A compound as defined in claim 5 which is8-amino-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 15.The compound as defined in claim 5 which is2,3,4,4a-tetrahydro-8-methyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 16.A compound as defined in claim 15 wherein R² is (lower)alkyl in the9-position.
 17. The compound as defined in claim 16 which is2,3,4,4a-tetrahydro-9-methyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one. 18.A compound as defined in claim 2 wherein R is hydrogen; R¹ is(lower)alkyl; and R² is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine,fluorine, trifluoromethyl, or amino.
 19. A compound as defined in claim18 wherein R and R² are each hydrogen and R¹ is (lower)alkyl.
 20. Thecompound as defined in claim 19 which is2,3,4,4a-tetrahydro-6-methyl-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one.21. A compound as defined in claim 2 wherein R is (lower)alkyl,phen(lower)alkyl, benzoyl(lower)alkyl, or p-halobenzyl(lower)alkyl; R¹is hydrogen; and R² is hydrogen, (lower)-alkyl, (lower)alkoxy, chlorine,fluorine, trifluoromethyl, or amino.
 22. A compound as defined in claim21 wherein R is (lower)alkyl, phen(lower)alkyl, benzoyl(lower)alkyl, orp-halobenzoyl(lower)alkyl, and R¹ and R² are each hydrogen.
 23. Acompound as defined in claim 22 which is2,3,4,4a-tetrahydro-3-(lower)alkyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.24. The compound as defined in claim 23 which is2,3,4,4a-tetrahydro-3-methyl-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one.25. The compound as defined in claim 22 which is3-[4-(4-fluorophenyl)-4-oxobutyl]2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one.26. The compound as defined in claim 22 which is2,3,4,4a-tetrahydro-2(2-phenethyl)-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.27. A compound as defined in claim 1 of the formula: ##STR8## wherein:R¹ and R³, independently, are hydrogen or (lower)alkyl;R⁴ is hydrogen,(lower)alkyl, (lower)alkoxy, chlorine, fluorine, or trifluoromethyl inthe 7-, 8-, or 9-position; or the non-toxic acid addition salts thereof.28. The compound as defined in claim 27 which is2,3,4,4a-,5,6-hexahydro-3-methyl-1H-pyrazino[1,2-a]quinoxaline.
 29. Acompound of the formula: ##STR9## wherein: R¹ is hydrogen or(lower)alkylR² is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine,fluorine, trifluoromethyl, amino, or trifluoroacetamido in the 7-, 8-,or 9-position.
 30. The compound as defined in claim 29 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.31. The compound as defined in claim 29 which is3-carbobenzoxy-7-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5-(6H)-one.32. A compound as defined in claim 29 which is3-carbobenzoxy-8-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.33. A compound as defined in claim 29 which is3-carbobenzoxy-9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxaline-5(6H)-one.34. A compound as defined in claim 29 which is3-carbobenzoxy-8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.35. A compound as defined in claim 29 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-8-methyl-1H-pyrazino[1,2a]-quinoxalin-5(6H)-one.36. A compound as defined in claim 29 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-9-methyl-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.37. A compound as defined in claim 29 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-8-trifluoromethyl-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one.38. A compound as defined in claim 29 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-8-(2,2,2-trifluoroacetamido)-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.39. A compound as defined in claim 29 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-9-methoxy-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.40. A compound as defined in claim 29 which is8amino-3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.41. The compound as defined in claim 29 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-6-methyl-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.42. An antihypertensive composition comprising (a) a hypotensiveeffective amount of a compound of the formula: ##STR10## wherein R ishydrogen, (lower)alkyl, phen(lower)alkyl, benzoyl(lower)alkyl, orp-halobenzoyl(lower)alkyl;R¹ is hydrogen or (lower)alkyl; R² is hydrogen(lower)alkyl, (lower)alkoxy, chlorine, fluorine, trifluoromethyl, oramino in the 7-, 8-, or 9-position; R³ is hydrogen or (lower)alkyl; andR⁴ is hydrogen, (lower)alkyl, (lower)alkoxy, chlorine, fluorine, ortrifluoromethyl in the 7-,8-, or 9-position; or the non-toxic acidaddition salts thereof; and (b) a pharmaceutically acceptable carrier;43. A composition as defined in claim 42 wherein the compound isselected from the group consistingof:2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one;2,3,4,4a-tetrahydro-6-methyl1H-pyrazino[1,2-a]quinoxaline-5(6H)-one;2,3,4,4a-tetrahydro-9-methoxy-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;7-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;8-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;2,3,4,4a-tetrahydro-8-trifluoromethyl-1-pyrazino[1,2-a[quinoxalin-5(6H)-one2,3,4,4a-tetrahydro-9-methyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;7-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one; and9-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-5(6H)-one.44. A composition as defined in claim 43 wherein the compound is2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.
 45. Acomposition as defined in claim 43 wherein the compound is2,3,4,4a-tetrahydro-6-methyl-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.46. A composition as defined in claim 43 wherein the compound is7-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]-quinoxalin-5(6H)-one. 47.A composition as defined in claim 43 wherein the compound is8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.48. A composition as defined in claim 43 wherein the compound is9-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one.